Alkoxyimino ether derivatives of 5-acyl-2(1H)-pyridinones

ABSTRACT

This invention relates to alkoxyimino ether derivatives of 5-acyl-2(1H)-pyridinones and to their use as cardiotonic agents useful in treating cardiac failure, and to the process useful in the preparation thereof.

This is a divisional of Ser. No. 476,993, filed Feb. 8, 1990, now U.S.Pat. No. 5,043,449 which is a divisional of Ser. No. 321,704, filed Mar.10, 1989, now U.S. Pat. No. 4,920,229 issued Apr. 24, 1990, which is adivisional of Ser. No. 166,147, filed Mar. 10, 1988, now U.S. Pat. No.4,849,522, issued Jul. 18, 1989, which is a divisional of Ser. No.834,692, filed Feb. 28, 1986, now U.S. Pat. No. 4,732,982, issued Mar.22, 1988, which is a continuation of Ser. No. 548,398, filed Nov. 3,1983, now abandoned.

This invention relates to alkoxyimino ether derivatives of5-acyl-2(1H)-pyridinones and to their use as cardiotonic agents usefulin treating cardiac failure, and to the process useful in thepreparation thereof.

More specifically, this invention relates to the pharmaceutically activealkoxyimino ethers having the formula ##STR1## and the pharmaceuticallyacceptable salts thereof wherein R₁ is C₁₋₁₀ alkyl,

R₃ is H, lower alkyl, --C.tbd.N, NH₂, CONH₂ and COOR with R beinghydrogen or lower alkyl,

R₄ is hydrogen or lower alkyl,

R₅ is C₁₋₁₀ alkyl, phenyl, X-substituted phenyl, pyridyl, thienyl,furyl, pyrrolyl and OR wherein R is hydrogen or lower alkyl, and X islower alkyl, lower alkoxy, lower alkylthio, lower alkyl sulfone, loweralkyl sulfoxide, halogen, nitro, lower alkanoyl, alkoxy carbonyl,carboxy, cyano, NH₂, CONH₂, COOR with R being hydrogen or lower alkyl,amidino, imidazol-2-yl, and CF₃, and

R₆ is hydrogen or R₅.

These compounds are useful as cardiotonics in the treatment of cardiacfailure and other conditions requiring strengthening of heart actionwith a cardiotonic agent.

As used herein, the term "alkyl" includes straight, branched-chain orcyclized hydrocarbyl radicals. Representative hydrocarbyls are radicalssuch as methyl, ethyl, propyl, isopropyl, cyclocyclopropyl, n-butyl,isobutyl, t-butyl, cyclobutyl, pentyl and hexyl, septyl, octyl, nonyland decyl, with methyl and n-butyl being preferred. The term"X"-substituted phenyl include those substituents preferably located inthe para position but includes the ortho and meta substituted compounds.The term "lower" when used to modify alkyl, alkoxy, alkylthio embracethose radicals having one to six carbon atoms. Inclusive of other "X"radicals are alkoxycarbonyl (--COO lower alkyl), lower alkanoyl(--CO-lower alkyl), amidino ##STR2## imidazol-2-yl ##STR3## lower alkylsulfone ##STR4## lower alkyl sulfoxide ##STR5## and halogeno preferablyincludes chloro and bromo but is embrasive of all members. The term"pyridyl" includes 2-, 3-, and 4-pyridyl, "furanyl" include 2- and3-furanyl, "thienyl" includes 2- and 3- i - , and "pyrryl" includes 2-and 3-(1H)-pyrryl.

The compounds of formula I are useful both in the free base form and inthe form of acid addition salts with both forms being within the purviewof this invention. The acid addition salts are simply a more convenientform for use and, in practice, use of the salt amounts to use of thefree base. The acids which can be used include those which produce, whencombined with the free base, pharmaceutically acceptable salts, that issalts whose anions are relatively inocuous to the animal organism inpharmaceutical doses of the salts. In practice, it is convenient to formsulfate, phosphate, methansulfate or lactate salts. Others are thosederived from mineral acids (e.g., hydrochloric), and organic acids suchas acetic acid, citric acid, tartaric acid, ethanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid and the like. The acidsalts are prepared by standard techniques such as by dissolving the freebase in aqueous or aqueous-alcohol solution or other suitable solventscontaining the appropriate acid and isolating by evaporating thesolution, or by reacting the free base and in an organic solvent inwhich case the salt separates directly or can be obtained byconcentration of the solution.

In general, the compounds of this invention are prepared by standardtechniques analogously known in the art. A convenient synthesis forpreparing the compounds of formula I conveniently involves the reactionof a 5-acyl-2(1H)-pyridinone (II) with the appropriate alkoxyamine,preferably in the form of an acid addition salt, according to standardoximination reaction conditions. In effecting the oximination, thealkoxyamine is contacted with a base (e.g., pyridine) to form an anionwhich is then condensed with the 5-acyl-2(1H)-pyridinone (II) by heatingthe reactants together in an inert solvent. The reaction proceeds wellat temperatures between room temperature and the reflux temperature ofthe reaction mixture. Reaction at reflux is preferred wherein anyart-recognized solvent, such as ethanol, may be utilized.

The foregoing reaction is depicted as follows: ##STR6## wherein R₁, R₃,R₄, R₅ and R₆ are as defined. Of course in those instances wherein the5-acyl-2(1H)pyridinone bears substituents which would be unstable underthe reaction conditions, then such substituent-bearing compounds wouldfirst be modified. Then, upon completion of the oximination reaction,the desired compounds may be obtained. Such procedures are well knownand represent standard techniques well known in the art.

The 5-acyl-2(1H)pyridinone intermediates (II) are prepared by standardtechniques analogously known in the art. A preferred synthesis forpreparing these intermediates conveniently involves the reaction of anappropriate 1-R₅ -3-R₆ -2-(1-dimethylamino-1-R₄-methylidenyl)-1,3-propanedione (III) with an appropriately R₃substituted acetoacetamide (IV) according to standard Michael additionaddition reaction conditions. Preferably, the substituted acetamide isreacted with sodium hydride, under argon in an inert organic solvent,(e.g., tetrahydrofuran) to form an anion which is then condensed withthe diketone (III) by heating the reactants together in an inert organicsolvent, preferably tetrahydrofuran and the like. Preferably, thetemperature of the reaction is about 50° C. although the reactionproceeds well at temperatures between room temperature and 100° C.Heating is effected over a period of several hours although it ispreferred to allow the reaction to proceed overnight. When R₅ and R₆ arenot the same a mixture of products are obtained which are separatedquite nicely by flash chromatography wherein the reaction productmixture is admixed with 60-200 mesh silica gel and the column is elutedwith an appropriate solvent system (e.g., 35% ethylacetate - 65%methylene chloride). The fractions of eluate are monitored by thin layerchromatography.

The foregoing reaction is depicted as follows: ##STR7## wherein R₄, R₅and R₆ are as previously R₃ " is cyano, --CO₂ H, lower alkyl or NH₂ ; R₃' is cyano, --CO₂ H, lower alkyl or --N═CH phenyl.

The 1-R₅ -3R₆ -2-[(1-dimethylamino)alkylidenyl]-1,3-propanediones (III)are readily prepared by condensing the appropriate R₅, R₆-1,3-propandiones with the appropriately R₄ substitutedN,N-dialkylamino-dialkoxy methane (e.g., dimethylformamide acetals)according to standard condensation reaction conditions such as, forexample, contacting equimolar quantities of the reactants together,optionally in an inert organic solvent and stirring the mixture for 1-12hours at about room temperature. This reaction is depicted as follows:##STR8## wherein R₄, R₅ and R₆ are as previously defined.

In those instances, wherein X is other than lower alkyl, hydroxy,alkoxy, halogen, nitro, cyano, amino, and R₃ is other than cyano, it ispreferred to prepare a compound of formula I wherein X is cyano, andthen, by the use of standard techniques, convert the cyano moiety to thedesired substituents. For example, the cyano moiety may be converted toa carboxyl moiety by hydrolyzing the nitrile with 6N hydrochloric acid,sulfuric and/or other mineral acids under standard conditions such as byheating at reflux temperatures for about 12-24 hours. The carboxylmoiety may be converted to an alkoxycarbonyl moiety by the standardFisher esterification procedure such as by heating thecarboxy-containing compounds with an appropriate alcohol in the presenceof an acid, e.g., 3% hydrochloric acid. The carboxamido-containingcompounds may be prepared by converting the alkoxycarbonyl moiety byheating the esters in the presence of ammonia or an appropriate amine,preferably in a pressure bomb at about 100°-150° C. in an inert solvent,e.g., benzene, toluene and the like. Alternatively, the carboxamidomoiety may be prepared by hydrolyzing a nitrile with concentratedsulfuric acid by heating on a steam bath at temperatures of about50°-100° C. In those instances wherein R₃ is cyano, it is preferred tohave the ultimately desired X substituent on the phenyl ring prior tothe Michael addition reaction between the 1-R₅ -3-R₆-1-dimethylamino-1-R₄ -methylidenyl)-1,3-propanedione and the cyanosubstituted acetamide.

In those instances wherein X is imidazol-2-yl, such compounds areprepared by a condensation reaction wherein the nitrile is heated tofrom about 150°-200° C. with ethylene diamine for about 2 hours. Theamidino compounds are prepared from corresponding nitriles wherein thenitrile is converted to an imino ether which is converted to the amidinomoiety by treating the imino ether with ammonia in alcohol attemperatures of about 0° C. room temperature. The sulfones andsulfoxides may be prepared from the alkylthio moiety by standardoxidation procedures.

In those instances wherein the R₃ substituent is hydrogen, it ispreferred to chemically remove a cyano moiety from a compound of formulaI by standard techniques such as by conversion of the cyano moiety to acarboxyl radical by treatment with a strong acid and then the compoundis decarboxylated. Alternatively, the carboxyl radical may converted toan alkyl moiety by standard Grignard reaction conditions.

The preparation of the compounds of formula I may be illustrated by thefollowing specific examples.

PREPARATION OF INTERMEDIATE 1-R₅ -3R₆ -2-(1-DIALKYLAMINO-1-R₄METHYLIDINYL)-1,3-PROPANDIONES Example 12-Dimethylaminomethylenyl-1-phenyl-1,3-butandione

A mixture of 1-benzoylacetone (24.00 g, 0.15 mole) and dimethylformamidedimethylacetal were stirred overnight at room temperature under argon.The resulting reddish-colored mixture was concentrated on the rotaryevaporator, then dissolved in THF (tetrahydrofuran). The resultingsolution was stirred and heated to boiling and slowly diluted withhexane. At the point of turbidity heating was discontinued. An orangegum precipitated and rapidly solidified. The mixture was chilled in anice bath and filtered yielding 25.25 g (78%) of2-(dimethlamino)-1-phenyl-1,3-butanedione m.pt. 72°-74° C.

Example 2 3-[(Dimethylamino)methylenyl]-2,4-pentanedione

A mixture of dimethylformamide dimethyl acetal (16.68 g, 0.136 mole) and2,4-pentanedione (13.65 g, 136 mole) was stirred overnight at roomtemperature under argon. The resulting red oil was concentrated on therotary evaporator to yield 20.15 g (86%) of3-[(Dimethylamino)methylenyl]-2,4-pentanedione.

Example 3 3-[(Dimethylamino)Methylene]-2,4-Octanedione

A mixture of 2,4-octanedione (7.11 g, 0.50 mole) and dimethylformamidedimethylacetal (7.15 g, 0.60 mole) was stirred overnight at roomtemperature under argon. The resulting red oil was concentrated on therotary evaporation then distilled on the kugelrohr at -15 mm, 140°-155°C. to yield 8.60 g (87%) of3-[(dimethylamino)methyleno]-2,4-octanodione.

Example 4 4-[(Dimethylamino)methylenyl]-3,5-heptanedione

A mixture of 3,5-heptanedione (6.41 g, 0.050 mole) and dimethylformamidedimethylacetal (6.27 g, 0.053 mole) were stirred at room temperatureovernight under argon. The resulting red liquid was concentrated on therotary evaporator to yield 8.60 g (99%) of4-[(Dimethylamino)methylenyl-3,5-heptanedione.

In a similar manner, by substituting the 1,3-propanediones of theforegoing examples with the appropriately substituted analogs thereofand by substantially following the procedures there is produced thefollowing intermediates:

1-(4-cyanophenyl)-2-(dimethylaminomethylenyl)-1,3-butandione,

1-(4-chlorophenyl)-2-(dimethylaminomethylenyl)-1,3-butandione,

1-(4-pyridyl)-2-(dimethylaminomethylenyl)-1,3-butandione,

1-(2-thienyl)-2-(dimethylaminomethylenyl)-1,3-butandione,

1-[2-(1-H-pyrryl)]-2-(dimethylaminomethylenyl)-1,3-butandione,

1-(3-furanyl)-2-(dimethylaminomethylenyl)-1,3-butandione,

1-(4-methoxyphenyl)-2-(dimethylaminomethylenyl)-1,3-butandione,

1-(4-methylphenyl)-2-(dimethylaminomethylenyl)-1,3-butandione,

1-(4-nitrophenyl)-2-(dimethylaminomethylenyl)-1,3-butandione,

1-(4-aminophenyl)-2-(dimethylaminomethylenyl)-1,3-butandione,

1-(2,4-dichlorophenyl)-2-(dimethylaminomethylenyl)-1,3-butandione,

1-(4-cyanophenyl)-2-[1-(dimethylamino)ethylidenyl]-1,3-butandione.

PREPARATION OF INTERMEDIATE 5-Acyl-2-(1H)Pyridinones Example 55Acetyl-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile

Cyanoacetamide (4.02 g, 0.05 mole) was added to a stirred suspension ofsodium hydride (1.2 g, 0.05 mole) in dry tetrahydrofuran (125 ml) underan argon blanket. The suspension was warmed to 50° C., allowed to coolto room temperature and then3-[(dimethylamino)-methylenyl-2,4-pentanedione (7.75 g, 0.050 mole)dissolved in 20 ml of dry THF was added to the suspension. Theheterogeneous mixture was heated overnight at 50° C. The reactionmixture was allowed to cool to room temperature and neutralized withacetic acid to PH 6, and concentrated on the rotary evaporator. Theresidue was extracted with a 50:50 methylene chloride - water mixtureand collected by filtration to yield 5.8 g (66%) of a tan solid.Recrystallization from EtOAC (ethyl acetate) gave 3.84 g (44%) of5-acetyl-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile m.pt.225°-226° C.

In a similar fashion, by modifying the reactants and by substantiallyfollowing the foregoing procedure there are produced:

5-propionyl-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile

5-n-butyroyl-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile

5-isobutyroyl-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile

5-n-caproyl-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile

5-n-heptanoyl-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile

5-capryloyl-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile

5-nonyloyl-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile

and their corresponding 6-ethyl homologs.

Example 6 5-Acetyl-1,2-dihydro-2-oxo-6-phenyl-3-pyridinecarbonitrile

Cyanoacetamide (2.50 g, 0.03 mole) was added to a stirred suspension ofsodium hydride in (150 ml) THF and warmed to 50° C. The mixture wasallowed to cool to room temperature then3-[(dimethylamino)methylenyl]-1-phenyl-1,3-butanedione (6.52 g, 0.03mole) dissolved in THF (20 ml) was added all at once. The suspension washeated and stirred at 50° C. overnight. The reaction mixture was allowedto cool to room temperature, treated with acetic acid to pH 6 andconcentrated on the rotary evaporator. Workup as in Example 5 gave 3.0 gof a yellow powder. The powder was mixed with 10 g of silica gel (60-200mesh) and flash chromatographed eluting with 25% EtOAC -75% CH₂ Cl₂collecting 50 ml fractions to yield 1.1 g of5-acetyl-1,2-dihydro-2-oxo-6-phenyl-3-pyridinecarbonitrile m.pt.259°-261° C. in fractions 11 to 20.

Example 7 5-Benzoyl-1,2-Dihydro-6-Methyl-2-Oxo-3-pyridinecarbonitrile

The chromatography in Example 6 gave 1.1 g of5-benzoyl-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile in fractions24 to 40 m.pt. 265°-261° C.

Example 8 3-Cyano-1,2-Dihydro-6-Methyl-2-Oxo-5-Pyridinecarboxylic acidethyl ester

Ethylacetoacetate (6.5 g, 0.050 mole) and dimethylformamide dimethylacetal (7.14 g, 0.060 mole) were stirred together under argon overnight.The resulting reddish oil was concentrated on the rotary evaporator andthe concentrate then dissolved in THF (10 ml) and quickly added to asuspension of cynaoacetamie (4.20 g, 0.050 mole) and sodium hydride inTHF (175 ml). The reaction mixture was heated and stirred overnight at50° C. The reaction mixture was neutralized to pH 6 with acetic acid andconcentrated on the rotary evaporator. The residue was triturated with a50:50 CH₂ Cl₂ --H₂ O mixture collected and recrystallized (EtOAC) giving4.7 g of 3-cyano-1,2-dihydro-6-methyl-2-oxo-5-pyridinecarboxylic acidethyl ester m.pt. 208°-210° C.

Example 9 5-(1-Oxopentyl)-1,2-Dihydro-6-Methyl-2-Oxo-3-PyridineCarbonitrile

3-[(Dimethylamino)methylenyl]-2,4-octanedione (7.29 g, 0.037 mole) wasadded to a stirred suspension or cyanoacetamide (3.36 g, 0.04 mole) andsodium hydride (1.0 g, 0.04 mole) and treated as above, to yield 4.97 g(61%) of an off white powder. Approximately 3.0 g of this powder wasmixed with 8.0 g of 60-200 mesh silica gel and flash chromatographedeluting with 35% EtOAC-65% CH₂ Cl₂ and collecting 65 ml fractions. 600mg of 5-(1-oxopentyl)-1,2-dihydro-6-methyl-2-oxo-3-pyridine carbonitrilem.pt. 216°-217° C. was collected in fractions 5 and 6.

Example 10 5-Acetyl-1,2-Dihydro-6-Butyl-2-Oxo-3-Pyridinecarbonitrile

The flash chromatography described in Example 9 was continued to give1.8 g of 5-acetyl-1,2-dihydro-6-butyl-2-oxo-3-pyridine carbonitrilem.pt. 195°-197° C. in fractions 12 to 25.

Example 115-(1-Oxopropyl)-6-Ethyl-1,2-Dihydro-2-Oxo-3-Pyridinecarbonitrile

4-[(Dimethylamino)methylenyl]-3,5-heptanedione dissolved in THF wasadded all at once to a suspension of cyanoacetamide (4.21 g, 0.050 mole)and sodium hydride (1.20 g, 0.050 mole) in dry THF (150 ml) under argonand, with constant stirring, heated at 50° C. overnight. The mixture wasbrought to pH 6 with acetic acid and concentrated on a rotaryevaporator. The residue was recrystallized (methanol) giving 4.0 g (40%)of 5-(1-oxopropyl)-6-ethyl-1,2-dihydro-2-oxo-3-pyridinecarbonitrilem.pt., 247°-248° C.

Example 126-Ethyl-1,2-Dihydro-5-[(4-Methylthio)benzoyl]-2-Oxo-3-Pyridinecarbonitrileand5-(1-Oxopropyl)-1,2-Dihydro-6-(4-Methylthiophenyl)-2-Oxo-3-Pyridinecarbonitrile

1-[4-((methylthio)phenyl)]-1,3-pentanedione (2.66 g, 0.12 mole) anddimethylformamide dimethylacetal (1.79 g, 0.015 mole was stirredovernight at room temperature. The resulting red oil was concentrated onthe rotary evaporator and the concentrate was dissolved in THF and addedto a suspension of cyanoacetamide (0.84 g, 0.010 mole) and sodiumhydride (0.25 g, 0.010 mole) in THF (50 ml), and, with constant stirringheated at 50° C. for 15 hours and cooled. The mixture was brought to pH6 with acetic acid and concentrated. The residue was dissolved in CH₂Cl₂, extracted with 5% NaHCO₃, washed with brine, separated, dried(MgSO₄) and filtered. Concentration on the rotary evaporator gave ayellow gum which upon trituration with Et₂ O solidified.Recrystallization (EtOAC) gave 1.37 g m.pt. 208°-210° C. The HPLC (uBondpack CN column, 55% MEOH/45% H₂ O) showed two peaks in roughly a40:60 ratio).

Example 13 5-Acetyl-6-Methyl-2(1H)-Pyridinone

5-acetyl-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile (2.32 g,0.013 mole) and concentrated HCl (50 ml) were heated and stirred atreflux under an argon atmosphere for 5 hours. Upon cooling to roomtemperature a solid precipitated. The solid was collected by filtrationand allowed to air dry. The dry solid (1.25 g) was heated to 280°-290°C. and maintained at this temperature for 7 minutes. The residue wasallowed to cool to room temperature then extracted into methylenechloride. Concentration of the methylene chloride solution followed byflash chromatography (50% methylene chloride--ethyl acetate) gave 0.46 gm.pt. 201°-202° C. (1:t 196°-198° C.).

Example 14 5-Acetyl-1,2-Dihydro-6-Methyl-2-Oxo-3-Pyridinecarboxylic Acid

To 100 ml 6 N hydrochloric acid is added 5.0 grams (0.028 mole) of5-acetyl-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile. The mixtureis stirred and refluxed for 20 hours. Evaporation of the solvent affordsthe title compound.

Example 15 5-Acetyl-1,2-Dihydro-6-Methyl-2-Oxo-3-Pyridinecarboxylic AcidEthylester

In 500 ml absolute alcohol is dissolved 5 grams5-acetyl-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarboxylic acid. Themixture is stirred and refluxed while a slow stream of dry hydrogenchloride is introduced. The reaction is allowed to proceed for 7 hoursafter which the solvent is evaporated and the residue is recrystallizedfrom alcohol to give the title compound.

Example 16 5-Acetyl-1,2-Dihydro-6-Methyl-2-Oxo-3-Pyridinecarboxamide

To 100 grams of concentrated sulfuric acid is added 10 g (0.056 mole) of5-acetyl-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile. The mixtureis stirred at 60° C. for 5 hours, cooled and then poured on 1 kg ice.The resulting solid is collected, washed with water and recrystallizedfrom ethanol to give the title compound.

Example 17 5-Acetyl-1,2-Dihydro-6-Methyl-2-Oxo-3-AminopyridineHydrochloride

A solution of 10.2 g of potassium hydroxide and 10.8 g of bromine in 100ml of water is stirred with 11.6 g (0.06 mole) of5-Acetyl-1,2-dihydro-6-methyl-2-oxo-3-pyridine carboxamide. The mixtureis heated to 60° C. for 1 hour and then treated with 14.4 g of potassiumhydroxide in 25 ml water and heated to 75° C. for 1 hour and cooled to0° C. The (free base) title compound precipitates, is collected andwashed with water. The material is suspended in ether and treated withdry hydrogen chloride gas to form the HCl salt.

Example 18 3,6-Dimethyl-5-Acetyl-1,2-Dihydro-3-2-oxo-pyridine Step A:5-Acetylethyleneketal-1,2-Dihydro-6-methyl-2-oxo-3-pyridinecarboxaldehyde

To toluene (100 ml) add5-acetyl-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile (17.6 g/0.1mol), thyleneglycol (6.2 g/0.1 mol) and p-toluenesulfonic acid (0.1 g),and heat, under reflux conditions, the resulting mixture until thetheoretical amount of water is distilled. Cool and wash the solvent withsodium bicarbonate solution. Dry (with sodium sulfate) and evaporate thesolvent and dissolve the residue in 100 ml THF. The resulting solutionis treated at room temperature with diisobutylaluminium hydride (0.1mol) for one hour and the reaction mixture quenched with water andextracted with ether. The ether extract is water-washed, dried andevaporation of the solvent yields the desired product of this step.

Step B: 5-Acetyl-1,2-dihydro-3,6-dimethyl-2-oxo-pyridine

In 150 ml of ethanol, dissolve 10 g (0.045 mol) of the product of Step Aand 1.0 g of 10% palladium on carbon. The resulting mixture ishydrogenated at 50° C. until 2 equivalents of hydrogen gas is taken up.The solution is filtered and the solvent is treated with 150 ml 6Nhydrochloric acid and heated to reflux for one hour. Evaporation of thesolvent yields the desired compound of this example.

Example 19 5-Acetyl-1,2-Dihydro-3-Propyl-6-Methyl-2-oxopyridine

In 200 ml of THF is dissolved 10 g (0.045 mol) of5-acetylethyleneketal-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarboxaldehyde,and to this solution is added 0.090 mol of ethylmagnesium bromide indimethylether and the solution is refluxed for two hours, quenched with10% NH₄ Cl solution. The aqueous phase is discarded, and the organicphase water-washed, dried (Na₂ SO₄), evaporated and the residuedissolved in 200 ml ethyl alcohol. 10% palladium on carbon was added andthe mixture hydrogenated at 50° C. until one equivalent of hydrogen (≅1hour) is taken up. The solution is filtered, and the solvent is treatedwith 150 ml 6N HCl and heated to reflux for one hour. Evaporation of thesolvent yields the desired compound of this example.

Example 201,2-Dihydro-5-[1-(Methoxyimino)ethyl]-6-Methyl-2-oxo-3-pyridinecarbonitrile

A mixture of 5-acetyl-6-methyl-2(1H)pyridinone (1.76 g, 0.010 mol),methoxyamine hydrochloride (0.90 g, 0.107 mol) and pyridine (5.0 ml)were heated and stirred in EtOH (150 ml) at reflux. The initiallyheterogeneous mixture cleared as everything went into solution. At theend of 2 hours a solid precipitated. The reaction mixture was allowed tocool to room temperature and the solid was collected by filtration.Recrystallization (EtOH) gave 0.70 g (35%) m.pt. 275°-285° C.

Example 211,2-Dihydro-5-[1-(methoxyimino)pentyl]-6-methyl-2-oxo-3-pyridinecarbonitrile

A mixture of1,2-dihydro-6-methyl-2-oxo-5-(1-oxopentyl)-3-pyridinecarbonitrile (0.70g, 0.0032 mol), methoxyamine hydrochloride (0.32 g, 0.0038 mol) andpyridine (2.0 ml) was heated and stirred at reflux in EtOH (30 ml)overnight. The solution was cooled to room temperature and concentratedon the rotary evaporator. The residue was diluted with H₂ O and theresulting solid collected by filtration. Recrystallization (MeOH-H₂ O)gave 0.38 g (48%) m.pt. 159-161.

Example 221,2-Dihydro-5-[1-(Methoxyimino)hexyl]-6-methyl-2-oxo-3-pyridinecarbonitrile

A mixture of1,2-dihydro-6-methyl-2-oxo-5-(1-oxohexyl)-3-pyridinecarbonitrile (0.80g, 0.0038 mol) and pyridine (2.0 ml) were heated and stirred at refluxovernight in EtOH (30.0 ml). The solution was allowed to cool to roomtemperature and the solvent was removed on the rotary evaporator. Thepasty residue was triturated with H₂ O, filtered and recrystallized(EtOH-H₂ O) giving 0.5 g (56%) m.pt. 159°-165° C. One morerecrystallization gave the analytical sample m.pt. 170°-171° C.

Example 23 6-Ethyl-5-[1-(Methoxyimino)propyl]-2(1H)-pyridinone

A mixture of 5-ethyl-5-(1-oxopropyl)-2-(1H)-pyridinone (1.0 g, 0.0056mol), methoxyamine hydrochloride (0.53 g, 0.0063 mol) and pyridine (3.0ml) were heated and stirred at reflux for 48 hours in EtOH (30 ml). Thereaction mixture was allowed to cool to room temperature andconcentrated to a viscous liquid on the rotary evaporator at 60° C. Theresidue solidified on cooling. The solid was triturated with H₂ O (50ml) and then collected by filtration to give 0.91 g, m.pt. 120°-125° C.One recrystallization (EtOH-H₂ O) gave 0.55 g (47%), m.pt. 129°-131° C.

In a similar manner, by substituting the reactants of Examples 20-23with the equivalent amounts of the appropriate alkoxyamine and theappropriate 5-acyl-1,2-6-(R₆)-2-oxo-pyridinone (particularly thoseprepared in Examples 1-19) and by substantially following the procedureof Examples 20-23 there may be produced the desired alkoxyimino ethersof Formula I and in particular the following compounds:

1,2-dihydro-5-[1-(methoxyimino)ethyl]-6-ethyl-2-oxo-3-pyridinecarbonitrile;

1,2-dihydro-5-[1-(methoxyimino)butyl]-6-ethyl-2-oxo-3-pyridinecarbonitrile;

1,2-dihydro-5-[1-(methoxyimino)pentyl]-6-ethyl-2-oxo-3-pyridinecarbonitrile;

1,2-dihydro-5-[1-(methoxyimino)hexyl]-6-ethyl-2-oxo-3-pyridinecarbonitrile;

1,2-dihydro-5-[1-(methoxyimino)ethyl]-6-methyl-2-oxo-3-pyridinecarbonitrile;

1,2-dihydro-5-[1-(methoxyimino)propyl]-6-methyl-2-oxo-3-pyridinecarbonitrile;

1,2-dihydro-5-[1-(methoxyimino)butyl]-6-methyl-2-oxo-3-pyridinecarbonitrile.

as well as the ethoxyimino, propoxyimino, butyroxyimino, homologs of theforegoing and the 3-position carboxylic acid, carboxylic acid alkylester, carbamate, amino, 3-hydrogen and 3-lower alkyl analogs (i.e.,3-pyridinecarboxylic acid ethyl esters, 3-pyridinecarboxamides,3-aminopyridines, pyridine and 3-alkylpyridine) of the foregoing.

The compounds of general Formula 1 may be used in the treatment ofcardiac failure including congestive heart failure, backward heartfailure, forward heart failure, left ventricular heart failure, or rightventricular heart failure or in the treatment of any other conditionwhich requires the strengthening of heart action with a cardiotonic.

The utility of Formula 1 compounds as cardiotonics may be determined byadministering the test compound (0.01-0.3 mg/kg) intravenously,intraperitoneally, intraduodenally or intragastrically in a suitablevehicle to a mongrel dog (either sex). The test dogs are anesthetizedand prepared by isolating a suitable artery (e.g., femoral or commoncarotid) and vein (e.g., femoral or external jugular) introducingpolyethylene catheters filled with 0.1% Heparin-Na to record arterialblood pressure and administer compounds, respectively. The chest isopened by splitting the sternum at the midline or by an incision at theleft fifth intercostal space, and a pericardial cradle is formed tosupport the heart. A Walton-Brodie strain gage is sutured to the rightor left ventricle to monitor myocardial contractile force. Anelectromagnetic flow probe may be placed around the root of theascending aorta for measuring cardiac output less coronary blood flow.Heart failure is induced by administering sodium pentobarbital (20 to 40mg/kg) followed by a continuous infusion of 1-2 mg/kg/min. orpropranalol hydrochloride (4 mg/kg) followed by a continuous infusion of0.18 mg/kg/min. to the blood perfusing the heart. Followingadministration of either of these cardiac depressants, the right atrialpressure dramatically increases and cardiac output is severelydepressed. Reversal of these effects by the test compound indicatescardiotonic activity.

The compounds may be administered in various manners to achieve thedesired effect. The compounds may be administered alone or in the formor pharmaceutical preparations to the patient being treated eitherorally or parenterally, that is, intravenously or intramuscularly. Theamount of compound administered will vary with the patient, the severityof the cardiac failure and the mode of administration.

For oral or parenteral administration the cardiotonically effectiveamount of compound is from about 0.01 mg/kg of patients body weight perday up to about 00 mg/kg of patient body weight per day and preferablyfrom about 0.01 mg/kg of patient body weight per day up to about 50mg/kg of patient body weight per day.

For oral administration a unit dosage may contain, for example, from 0.1to 750 mg of the active ingredient, preferably about 0.5 to 500 mg ofthe active ingredient. For parenteral administration a unit dosage maycontain, for example, from 0.1 to 250 mg of the active ingredient,preferably about 0.5 to 100. Repetitive daily administration of thecompounds may be desired and will vary with the condition of the patientand the mode of administration.

As used herein the term patient is taken to mean warm blooded animals,for example, birds, such as chickens and turkeys, and mammals, such asprimates, humans, sheep, horses, bovine cows and bulls, pigs, dogs,cats, rats and mice.

For oral administration the compounds can be formulated into solid orliquid preparations such as capsules, pills, tablets, troches, powders,solutions, suspensions or emulsions. The solid unit dosage forms can bea capsule which can be of the ordinary gelatin type containing, forexample, lubricants and inert filler, such as lactose, sucrose andcornstarch. In another embodiment the compounds of general Formula 1 canbe tableted with conventional tablet bases such as lactose, sucrose andcornstarch in combination with binders, such as acacia, cornstarch orgelatin, disintegrating agents such as potato starch or alginic acid,and a lubricant such as stearic acid or magnesium stearate.

For parenteral administration the compounds may be administered asinjectable dosages of a solution or suspension of the compound in aphysiologically acceptable diluent with a pharmaceutical carrier whichcan be a sterile liquid such as water, alcohols, oils and otheracceptable organic solvents with or without the addition of a surfactantand other pharmaceutically acceptable adjuvants. Illustrative of oilswhich can be employed in these preparations are those of petroleum,animal, vegetable, or synthetic origin, for example, peanut oil, soybeanoil and mineral oil. In general, water, saline, aqueous dextrose andrelated sugar solutions, ethanol and glycols such as propylene glycol orpolyethylene glycol or 2-pyrrolidone are preferred liquid carriers,particularly for injectable solutions.

The compounds can be administered in the form of a depot injection orimplant preparation which may be formulated in such a manner as topermit a sustained release of the active ingredient. The activeingredient can be compressed into pellets or small cylinders andimplanted subcutaneously or intramuscularly as depot injections orimplants. Implants may employ inert materials such as biodegradablepolymers or synthetic silicones, for example, Silastic, a siliconerubber manufactured by the Dow-Corning Corporation.

As is true in many large classes of compounds certain subgeneric membersand certain specific members of the class are preferred for thepharmaceutical activity in treating disease states in man. In thisinstance the preferred compounds of formula I are those wherein R₅ islower alkyl. The preferred R₃ substituent is cyano, hydrogen, loweralkyl or amino. The preferred R₄ substituent is hydrogen, the preferredR₆ substituents are either ethyl or methyl and the preferred R₁ ismethyl or ethyl. The preferred compounds are those wherein R₃ ishydrogen or cyano, R₄ is hydrogen, R₆ is methyl or ethyl and R₅ is anystraight chain hydrocarbyl radical, and R₁ is methyl and ethyl with thespecific compounds most preferred being:

1,2-dihydro-5-[1-(methoxyimino)ethyl]-6-methyl-2-oxo-3-pyridinecarbonitrile;

1,2-dihydro-5-[1-(methoxyimino)propyl]-6-methyl-2-oxo-3-pyridinecarbonitrile;

1,2-dihydro-5-[1-(methoxyimino)butyl]-6-methyl-2-oxo-3-pyridinecarbonitrile;

1,2-dihydro-5-[1-(methoxyimino)pentyl]-6-methyl-2-oxo-3-pyridinecarbonitrile;

1,2-dihydro-5-[1-(methoxyimino)hexyl]-6-methyl-2-oxo-3-pyridinecarbonitrile;

1,2-dihydro-5-[1-(methoxyimino)heptanyl]-6-methyl-2-oxo-3-pyridinecarbonitrile;

1,2-dihydro-5-[1-(methoxyimino)ethyl]-6-ethyl-2-oxo-3-pyridinecarbonitrile;

1,2-dihydro-5-[1-(methoxyimino)propyl]-6-ethyl-2-oxo-3-pyridinecarbonitrile;

1,2-dihydro-5-[1-(methoxyimino)butyl]-6-ethyl-2-oxo-3-pyridinecarbonitrile;

1,2-dihydro-5-[1-(methoxyimino)pentyl]-6-ethyl-2-oxo-3-pyridinecarbonitrile;

1,2-dihydro-5-[1-(methoxyimino)hexyl]-6-ethyl-2-oxo-3-pyridinecarbonitrile;

1,2-dihydro-5-[1-(methoxyimino)heptanyl]-6-ethyl-2-oxo-3-pyridinecarbonitrile,

and the 3H analogs (i.e., the1,2-dihydro-5-[1-(alkoxyimino)alkyl]-6-alkyl-2-(1H)-pyridinones) of theforegoing specific compounds.

We claim:
 1. A compound of the formula: ##STR9## or a pharmaceuticallyacceptable salt thereof, wherein R₁ is C₁₋₁₀ alkyl,R₃ is H, lower alkyl,--C.tbd.N, --NH₂, --CONH₂ and --COOR with R being hydrogen or loweralkyl, R₄ is hydrogen or a lower alkyl R₅ is pyridyl, and R₆ is pyridyl.2. A compound of claim 1 wherein R₃ is cyano.
 3. A compound of claim 2wherein R₄ is hydrogen.
 4. A compound of claim 2 wherein R₁ is methyl.